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Isradipine

Class: Dihydropyridines
- Calcium-Channel Blocking Agents, Dihydropyridine
- Calcium Antagonists
VA Class: CV200
Chemical Name: 4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester
Molecular Formula: C19H21N3O5
CAS Number: 75695-93-1

Medically reviewed by Drugs.com. Last updated on Apr 8, 2019.

Introduction

Calcium-channel blocking agent; dihydropyridine derivative.1 2 3 4 7

Uses for Isradipine

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 2 3 4 6 7 13 14 15 1200

Calcium-channel blockers are recommended as one of several preferred agents for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics.501 502 503 504 1200 While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 504 1200 1213

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).501 502 503 504 515 1200 1201

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.1200 (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

Table 1. ACC/AHA BP Classification in Adults1200

Category

SBP (mm Hg)

DBP (mm Hg)

Normal

<120

and

<80

Elevated

120–129

and

<80

Hypertension, Stage 1

130–139

or

80–89

Hypertension, Stage 2

≥140

or

≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.1200 However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.501 503 504 505 506 507 508 515 523 526 530 1200 1201 1207 1209 1222 1223 1229

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200 In addition, an SBP goal of <130 mm Hg is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.1200 These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.1200 1202 1210

Other hypertension guidelines generally have based target BP goals on age and comorbidities.501 504 536 Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients501 504 536 compared with those recommended by the 2017 ACC/AHA hypertension guideline.1200

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.1222 1223 1224 1229

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.1200 1220 1229

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.1200 1207 ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.1200

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).1200

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.1200

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.1200 Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.502 1200

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.1200 Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.1200

Calcium-channel blockers may be beneficial in hypertensive patients with certain coexisting conditions (e.g., ischemic heart disease)523 and in geriatric patients, including those with isolated systolic hypertension.502 510 1200

Calcium-channel blockers may be particularly useful in black patients with hypertension;77 78 1250 1251 1252 1253 1254 1255 such patients generally respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).501 504 1200 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.1200

Use of the currently available conventional dosage form for acute management of hypertensive crises not established.4

Isradipine has been used for rapid reduction of BP in children and adolescents with severe hypertension.83 1150

Isradipine Dosage and Administration

General

BP Monitoring and Treatment Goals

  • Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.1200

  • If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.1200 1216

  • If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, thiazide diuretic).1200 1216 Many patients will require ≥2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved with 2 antihypertensive agents, add a third drug.1200 1216 1220

Administration

Oral Administration

Conventional Capsules

Administer orally twice daily without regard to meals.1 22

Reconstitution

Preparation of extemporaneous suspension containing isradipine 1 mg/mL: Open twenty-four 5-mg capsules and grind contents to a fine powder with a mortar and pestle;81 levigate with a small amount of glycerin to form a paste.81 Add simple syrup in increasing amounts while mixing thoroughly; transfer suspension to a graduated cylinder.81 Add any remaining drug in the mortar to the graduated container; the final volume of the suspension should be 120 mL.81 Transfer suspension to an amber bottle.81 Shake well before each use.81

Dosage

Pediatric Patients

Hypertension
Oral

Some experts recommend an initial dosage of 0.05–0.1 mg/kg 2–3 times daily as conventional capsules.1150 Experts state that drug should be initiated at the low end of the dosage range; dosage may be increased every 2–4 weeks until BP is controlled, maximum dosage is reached (0.6 mg/kg [up to 10 mg] daily), or adverse effects occur.1150

Severe Hypertension
Rapid Reduction of BP
Oral

Some experts recommend a dosage of 0.05–0.1 mg/kg (up to 5 mg) every 6–8 hours.1150

Adults

Hypertension
Oral

Initially, 1.25–2.5 mg twice daily 1 2 3 4 7 14 15 16 as monotherapy or when added to thiazide diuretic therapy.1

Full hypotensive effect may not be seen for 2–4 weeks.1 If BP control is inadequate after this period, increase dosage in increments of 5 mg daily at intervals of 2–4 weeks, up to a maximum of 20 mg daily, according to patient’s BP response.1 4 Some experts recommend usual dosage range of 5–10 mg daily given in 2 divided doses.1200

Dosages >10 mg daily usually do not result in further improvement in BP control and may increase risk of adverse effects.1 4

Prescribing Limits

Pediatric Patients

Hypertension
Oral

Maximum 0.6 mg/kg (up to 10 mg) daily.1150

Adults

Hypertension
Oral

Maximum 20 mg daily.1 4

Special Populations

Hepatic Impairment

Some clinicians recommend dosage modification (i.e., reduced dosage) and careful titration,3 21 but the manufacturer recommends usual initial adult dosage.1 4 7

Renal Impairment

Dosage modification not necessary.1 4 7

Geriatric Patients

Initial dosage modification not necessary,1 3 4 7 16 20 but slower dosage escalation recommended;3 20 BP may be adequately controlled with relatively low dosages and once-daily dosing.2 3 16

Cautions for Isradipine

Contraindications

  • Known hypersensitivity to isradipine or any ingredient in the formulation.1

Warnings/Precautions

General Precautions

Hypotension

Possible symptomatic hypotension.1 Carefully monitor BP, especially during therapy initiation or dosage increase.1

Heart Failure

May precipitate or worsen heart failure.1 16 18 Use with caution and titrate dosage carefully, especially in those receiving concomitant β-adrenergic blocking agents.1 16 18

Angina

Frequency, duration, and severity of angina may rarely increase during therapy.3 14 18

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether isradipine is distributed into milk; discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy remain to be fully established in children;1 22 however, some experts have recommended dosages for hypertension based on clinical experience.1150

Common Adverse Effects

Headache, dizziness, peripheral edema, palpitation, tachycardia, flushing, chest pain.1 2 3 4 10 11 13 14 15 16 17 18 19 20 21 22 23 24 25 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 51 52 53

Interactions for Isradipine

Appears to be metabolized by CYP3A4.1

Specific Drugs

Drug

Interaction

Comments

Cimetidine

Increased peak plasma concentrations and AUC of isradipine1

Monitor carefully; reduction of isradipine dosage may be required1

Digoxin

Pharmacokinetic interaction unlikely1

Fentanyl

Possible severe hypotension during fentanyl anesthesia with concomitant use of a β- blocker and a calcium channel blocker1

Increase volume of circulating fluids if hypotension occurs1

Hydrochlorothiazide

Pharmacokinetic interaction unlikely1

Nitroglycerin

Pharmacokinetic interaction unlikely1

Propranolol

Increased rate of absorption, AUC, and peak plasma concentrations of propranolol observed with single doses; no substantial effect on either drug under steady-state conditions1

Rifampin

Increased isradipine metabolism and clearance; reduction of isradipine concentrations to below detectable levels1

Isradipine concentrations and therapeutic effects will be markedly reduced or abolished with concomitant use1

Warfarin

Pharmacokinetic or pharmacodynamic interaction unlikely

Isradipine Pharmacokinetics

Absorption

Bioavailability

90–95% absorbed following oral administration, with peak plasma isradipine concentrations attained in about 1.5 hours.1

Bioavailability is approximately 15–24% due to first-pass metabolism.1

Onset

After a single dose, reduction in supine and standing BP occurs within 2–3 hours.1

Duration

Effects persist for >12 hours after administration.1

Food

Food decreases time to peak plasma concentration by about 1 hour.1

Special Populations

In patients with hepatic impairment, peak plasma concentration and AUC are increased by 32 and 52%, respectively.1

In patients with mild renal impairment (Clcr 30–80 mL/min), AUC is increased by 45%; however, in patients with severe renal failure (Clcr <10 mL/min) who have been on hemodialysis, AUC is decreased by 20–50%.1

In geriatric patients, peak plasma concentration and AUC are increased by 13 and 40%, respectively.1

Distribution

Extent

It is not known whether isradipine is distributed into milk.1

Plasma Protein Binding

95%.1

Elimination

Metabolism

Completely metabolized in the liver, apparently by CYP3A4, to inactive metabolites.1

Elimination Route

Excreted in urine (60–65%) and feces (25–30%).1

Half-life

Biphasic; initial half-life is 1.5–2 hours and terminal elimination half-life is approximately 8 hours.1

Stability

Storage

Oral

Conventional Capsules

Tight, light-resistant containers at 20–25°C.82

Extemporaneous Suspension

Isradipine 1 mg/mL in simple syrup (see Reconstitution under Dosage and Administration): Stable for 35 days when refrigerated.81

Actions

  • Inhibits transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium concentrations.1

  • Peripheral arterial vasodilator; acts directly on vascular smooth muscle causing reduction in peripheral vascular resistance (afterload) and BP.1

Advice to Patients

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Isradipine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

2.5 mg*

Isradipine Capsules

5 mg*

Isradipine Capsules

AHFS DI Essentials™. © Copyright 2020, Selected Revisions April 8, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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